Parkinson's
30 years fighting Parkinson's disease through Personalised Medicine and Genomics.
What is Parkinson's disease?
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting between 1 and 3% of the population over the age of 65 in Western countries. It is a chronic, progressive and disabling movement disorder whose aetiology or cause is currently unknown, although it is thought to have a multifactorial origin.
Parkinson's disease belongs to the group of parkinsonian syndromes, characterised in its clinical manifestations by:
- Shaking
- Muscle stiffness
- Bradykinesia (slowness of movement) postural disturbances
- The disease may also be accompanied by psychiatric manifestations (visual hallucinations and depression), although these are not always present.
The lesion leading to the disease is the disruption of the dopaminergic pathway between the substantia nigra and the striatum of the brain (nigrostriatal dopaminergic pathway) leading to a decrease in the neurotransmitter dopamine.
Parkinson's disease causes and risk factors
PD is a movement disorder characterised by tremor, rigidity and bradykinesia. These symptoms appear decades after the process of neuronal death has begun.
This progressive destruction mainly affects the dopaminergic neurons of the basal ganglia, especially the nigrostriatal pathways that are organised in the compact part of the substantia nigra. This degeneration and death of dopaminergic neurons leads to the loss of the neurotransmitter dopamine in the affected areas of the brain, which is responsible for the characteristic symptoms of the disease.
In addition to this neuropathological finding, another very characteristic feature of the disease is the presence of Lewy bodies in dopaminergic neurons. These are abnormal accumulations of proteins, mainly alpha-synuclein, an important protein in the normal functioning of our brain, especially in neuronal synapses, through which neurons communicate. For as yet unknown reasons, alpha-synuclein loses its original structure (the functions of proteins are determined by their structure, rather like a building) and accumulates to form Lewy bodies.
Among the main risk factors for developing Parkinson's is age, as it has been shown to be the most important factor in the development of the disease, with an average onset at approximately 50 to 60 years of age.
Other importantOther important risk factors are:
- Family history
- Continued exposure to environmental neurotoxicants, pharmaceuticals, pesticides
- Traumatic micro-injuries
- Microinfarcts in the brain
- Oxidative processes that enhance the formation of free radicals and the failure of anti-oxidative systems.
- Endogenous or reactive neuroimmune and neuroinflammatory reactions damaging dopaminergic neurons
- Dysfunction of the ubiquitin-proteasome system, unable to adequately process proteins whose conformational changes turn them into endogenous neurotoxicity elements.
- Genomic defects in several genes distributed across the human genome
- Epigenetic changes (DNA methylation, chromatin alterations, dysfunction of microRNAs)
It is highly likely, as with other neurodegenerative diseases, that the confluence of genomic vulnerability factors, with epigenetic changes, and environmental factors, is the main cause of the growing impact of Parkinson's disease in our society today.
There is clear evidence that the neurodegenerative process responsible for PD begins decades before the onset of PD symptoms, so that by the time the motor impairment of PD begins, billions of dopaminergic neurons have already died, and neuro-regeneration is currently impossible.
Future treatments must therefore aim both to protect dopaminergic neurons from dying and to mitigate the psychomotor component that accompanies dopaminergic neurodegeneration.
Age is a clear risk factor, with the average age of onset being between 55-60 years. Thus, the prevalence increases exponentially from the sixth decade of life onwards, from 41 cases per 100,000 in the fourth decade of life to more than 1,900 cases per 100,000 in people over 80 years of age. When PD appears before the age of 50, it is called Early Onset PD.
Numerous scientific studies have shown a higher frequency of Parkinson's disease among relatives of an affected person compared to those with no family history of the disease. The level of genetic contribution in Parkinson's appears to be determined by the age of onset of the disease. The earlier the onset of the disease, the greater the chance of having a family member affected.
The genetic component associated with familial forms of the disease corresponds to approximately 10%, while the remaining 90% are classified as sporadic, apparently non-familial cases.
It is thought that more than half a thousand genes may be involved in PD; of which about 18 loci (PARK1-18) distributed across the human genome are pathogenic and potentially causative for heritable forms of PD (a-synuclein, LRRK2, Parkin, PINK1, DJ-1, ATP13A2), while other loci (e. g. LRRK2, MAPT, SCA1, SCA2, spatacsin, POLG1, GBA) appear to be more elements of genetic susceptibility or vulnerability, associated with apparently sporadic forms of PD, whose familial component is undeniable, despite its apparent sporadicity.
All these genes are under the influence of epigenetic machinery that regulates their expression in different tissues and may contribute to the selective neurodegeneration of dopaminergic neurons in the substantia nigra.
A recent study has established population patterns of high susceptibility to pesticides based on the genomic profile of individuals, with special emphasis on genes responsible for pesticide metabolism (PON1), transporter genes that regulate the passage of xenobiotic agents across the blood-brain barrier (ABCB1), dopamine transporter genes (DAT/SLC6A3) or regulators of its metabolism (ALDH2), genes influencing mitochondrial oxidative/nitrosative function (NOS1), proteasome inhibitors (SKP1), or regulators of immune function (HLA-DR).
Parkinson's disease is a genetically complex disease caused by the interaction of multiple environmental factors and variations in different genes. These genetic variants determine susceptibility or resistance to the disease and response to treatment.
Due to the interaction between genes and environment, complex diseases can be prevented by acting on environmental factors with an appropriate prevention plan.
A person's chance of developing Parkinson's is greater when there is a family history of the disease.
At EuroEspes we have designed a genetic risk panel for 22 DNA markers related to Parkinson's disease where the patient's risk profile is defined as the carrier status of risk variants. This tool contributes to a physician’s better understanding of the patient's individual characteristics in terms of symptoms, responsiveness to treatment and helps them decide on the best way to approach the problem in a personalised way.
Symptoms and clinical picture of Parkinson's disease
The clinical picture of PD is highly heterogeneous. Understanding the factors that determine disease progression in individual patients could have important implications for prognosis, clinical trial design, and future strategies for individualised therapy. A substantial component of Parkinson's risk is inheritable, suggesting that genetic variability may also affect the clinical phenotype once the disease manifests.
Parkison's disease is characterised by the selective loss of dopaminergic neurons, resulting in motor and cognitive impairments, including:
- Tremors, these are slow, rhythmic movements. Predominant at rest and decreases when making a voluntary movement.
- Muscle stiffness, muscle tension and difficulty in relaxation.
- Bradykinesia, slowness of voluntary and automatic movements. This means that simple tasks are difficult and take longer. Steps may be shorter during walking. It may be difficult to get up from a chair. There may be shuffling of the feet while walking.
- Postural and balanceabnormalities, forward tilting of the trunk and head. Elbows and knees appear bent.
- Loss of automatic movements, reduced ability to perform unconscious movements such as blinking, smiling or swinging arms while walking.
- Changes in speech, speaking softly, more monotone.
- Changes in facial expression, loss of expressiveness.
- Changes in handwriting, difficulty in writing.
- Sleep disorders, loss of normal atonia during REM sleep.
- Ocular symptoms: loss of visual acuity, saccadic movements (rapid eye movements), dry eyes, double vision, lack of focus, presence of visual hallucinations, among others.
- Difficulties in eating, chewing, and swallowing.
- Impaired sense of smell (anosmia).
- Symptoms of autonomic dysfunction (constipation, sweating disturbances, sexual dysfunction, seborrhoeic dermatitis, urinary incontinence).
- General feeling of weakness, malaise, or tiredness.
- Depression or anhedonia (lack of reactivity to usually pleasurable stimuli).
- Slowness of thought and diminished intellectual capacity.
- Muscle and joint pain.
In many cases, Parkinson's coexists with depression; in more than 50% of cases it is associated withanxiety problems; and over the years, becuase of organic wear and tear or personal predisposition, it can evolve into a dementia of the dementia-Parkinson's complex type or other forms of dementia. To this must be added many other age-related complications must be added, which are superimposed on the disability caused by Parkinson's disease itself.
A study carried out by the Spanish Parkinson's Federation shows that more than half of the people with Parkinson's disease in Spain take an average of between 1 and 5 years from the first symptom of the disease until they are diagnosed. In fact, 19% wait more than 5 years to receive a definitive diagnosis. During this time, people with Parkinson's and their carers make a fruitless journey from consultation to consultation until a diagnosis is made. Currently, the diagnosis of patients with Parkinson's disease is mainly based on clinical observation of symptoms and is supported by a series of imaging tests. Because of this, the diagnosis of these patients usually occurs when the patient is already at an advanced stage of the disease, when therapeutic opportunities are already limited.
A good PD diagnosis should be based on a protocol that includes:
- Anamnesis, examination and clinical neuropsychiatric examination and exploration.
- Blood and urine tests .
- Psychometric assessment.
- Radiological static and functional neuroimagingradiological tests.
- Cerebral and cerebrovascularfunction tests.
- Genetic testing and pharmacogenetic profiling. Identification of possible genomic alterations in genes associated with familial PD, or the presence of susceptibility genes. It is also very important to know the patient's pharmacogenetic profile in order to know the response to treatment.
At present there is no biological marker that can diagnose Parkinson's disease with certainty and speed. There is no value in a blood test or physiological test to confirm it. It is a clinical diagnosis, i.e., based on clinical history, physical and neurological examination of the person and the presence of certain symptoms or the absence of others. The latest advances in diagnosis such as functional imaging tests, neuropsychological tests, among others, can help in the diagnosis from a suspicion based on the clinical evaluation of the symptoms and signs presented by the patient. In families in which there is hereditary Parkinson's disease attributable to a mutation in one of the genes responsible for this disease, the demonstration of this mutation in a certain member can allow for their identification as a carrier of the disease and, if they present compatible symptoms, as a person with Parkinson's disease.
There is currently no biological marker, blood test value or physiological test to confirm this.
The identification of biomarkers for the diagnosis and monitoring of these patients is therefore of great importance. The identification and validation of these biomarkers would help both in diagnosis and in the choice of the ideal treatment (precision or personalised medicine) and in monitoring the patient's response to the treatment provided.
The primary objective is to find biomarkers for early diagnosis, which will identify the risk of this disease 10 years before it occurs, thus enabling early diagnosis and treatment, thereby greatly improving the patient's quality of life.
Treatments and therapies
The unsatisfactory effects of conventional antiparkinsonian drugs have prompted the search for new therapeutic alternatives.
Classic treatments for Parkinson's disease include drug therapy, deep brain stimulation, and physiotherapy. Conventional drug treatmentsThe following products, aimed at mitigating motor symptomatology, are as follows:
L-DOPA (levodopa). Precursor of dopamine synthesis. From a therapeutic perspective, the introduction of levodopa (L-DOPA) in 1960 represented a breakthrough in the treatment of PD, and it remains the most effective symptomatic therapy in Parkinsonian disorders. However, chronic administration of L-DOPA and other antiparkinsonian drugs causes serious side effects that should have special attention paid to them by the medical community. Due to this, new compounds devoid of psychomotor, biochemical, neuropsychiatric, and autonomic complications are under experimental scrutiny in preclinical studies and clinical trials.
Dopaminergic agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine). They are useful in monotherapy in early stages of the disease or in association with levodopa, as they have less risk of developing motor complications than levodopa.
Monoamine oxidase inhibitors, MAOIs (selegiline, rasagiline).
Catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). These drugs reduce the metabolism of levodopa and therefore increase its half-life and therapeutic effects, reducing the need for levodopa by up to 30%.
One of the most relevant complications of chronic treatment with L-DOPA and other dopaminergic agents is the "wearing-off" phenomenon, characterized by motor fluctuations and dyskinesia.
To circumvent this problem, complementary strategies have been developed with dopaminergic and non-dopaminergic agents, such as new formulations of L-DOPA, COMT inhibitors (opicapone), dopaminergic agonists, adenosine A2A antagonists (istradephylline, preladenant, tozadenant), glutamatergic antangonists (NMDA, N-methyl-d-aspartate), serotonergic agents (eltoprazine), and mGluR5 glutamate receptor modulators (mavoglurant). However, none of these agents have been shown to be sufficiently effective.
Polypharmacy with antidepressants, antipsychotics, urological agents, analgesics, antihistamines, and acetylcholinesterase inhibitors contribute to the development of complications, undesirable drug interactions, and anticholinergic conditions. In addition, there are gastrointestinal complications (constipation, hypersalivation, dysphagia, chewing difficulties), cardiovascular problems, neuroendocrine disturbances, and psychiatric disorders associated with chronic use of conventional antiparkinsonian drugs.
An additional complication is Pisa syndrome, which is characterised by a sustained abnormal posture with flexion of the body and head to one side and axial rotation of the trunk and is associated with the use of antipsychotics.
A bad habit in the management of psychotic symptoms in Parkinsonian patients is the administration of atypical neuroleptics (such as quetiapine), which contribute to aggravating motor symptoms, due to their antidopaminergic effect, and to increasing the side effects intrinsic to the antipsychotic agents themselves.
In order to provide effective medical treatment, the main objective is to provide the patient with control of signs and symptoms for as long as possible and to minimise adverse effects.
Symptomatic drug therapies usually provide some control over the motor signs of PD for the 4-6 years of life following diagnosis, mainly through the use of levodopa/carbidopa as a standard prescription for symptomatic treatment, while monoamine oxidase-B (MAO) inhibitor drugs may be considered more effective for treatment in the early stages of the disease.
However, other dopamine agonists (e.g., ropinirole, pramipexole) can be used as a monotherapy in early disease and as moderately effective adjuvant therapy in advanced stages of the disease. To minimise tremor symptoms, a second line of anticholinergic agents (e.g., trihexyphenidyl, benztropine) are also commonly prescribed.
Currently, the major challenges in the treatment of PD are, on the one hand, to protect dopaminergic neurons in order to prevent or halt the progression of the disease and, on the other hand, to find a treatment capable of rescuing neurons at risk of dying.
The unsatisfactory effects of conventional antiparkinsonian drugs have prompted the search for new therapeutic alternatives. The use of natural substances and derived bioproducts (i.e., Vicia faba, Mucuna pruriens, Siegesbeckia pubescens, Sophora flavescens, Carthamus tinctorius, Curcuma longa, Huperzia selago, Diphasiastrum complanatum, Centella asiatica, Sulforaphane, Oleuropein, Resveratrol and other polyphenols, flavonoids, ginsenosides and caffeine) has been restarted.
Over the last decade, nutraceuticals have gained prominence due to their multifaceted effects, with demonstrated efficacy on multiple pathways through a slow but more physiological action and without causing adverse effects. The results of several investigations support the idea that, apart from the prevention of neuronal damage, nutraceuticals can potentially attenuate the ongoing progression of neuronal destruction.
The use of nutraceuticals derived from certain plants were shown, in experimental studies, to inhibit enzymes that otherwise phosphorylate the α-synuclein protein, such as kinases (Cumin thymoquinone-black), casein kinase II (ellagic acid), Gprk2GRK2/5, or proteases such as calpains and lysosomal cysteine protease cysteine, casein kinase II (ellagic acid), Gprk2GRK2/5 or proteases such as calpains and lysosomal cysteine protease. This prevents the tendency of α-synuclein to aggregate or form truncated α-synuclein toxins. Since the use of nutraceuticals presents a valid therapeutic perspective that has not yet been fully appreciated by the scientific community, it is only fair to highlight the multiple properties of new plant-derived nutraceuticals.
E-PodoFavalin-15999 (AtreMorine®) is a novel biopharmaceutical compound obtained by non-denaturing biotechnological processes from structural components of the plant Vicia faba L.(natural source of L-dopa, a precursor of the neurotransmitter dopamine). This compound has demonstrated a neuroprotective effect on dopaminergic neurons in the substantia nigra pars compacta (brain region affected in PD) in animal models of PD.
Clinical studies indicate that AtreMorine® is a powerful dopamine and noradrenaline enhancer in Parkinsonian patients.
AtreMorine®is a good option to minimise the "wearing-off" phenomenon, prolonging the effect of conventional antiparkinsonian drugs at low doses, and, above all, to protect dopaminergic neurons against the process of premature death.
The powerful prodopaminergic effect of AtreMorine®, with a 200-300-fold increase in dopamine over baseline levels, is also regulated by pharmacogenetic factors, so that its therapeutic response depends on the pharmacogenetic profile of each patient. In addition to a high L-dopa content (between 20 and 25 mg/g of AtreMorine®), AtreMorine® also contains other biologically active compounds such as phytosterols and carotenoid pigments.
The scientific community's priority objectives for combating Parkinson's disease are as follows:
The search for reliable biomarkers to identify the risk of developing PD and to be able to implement prophylactic programmes with a preventive capacity.
The optimisation of the therapeutic effect of available drugs by personalising drug treatment with pharmacogenetic strategies to improve efficacy and reduce toxicity.
The development of new drugs and/or bioproducts capable of protecting dopaminergic neurons from the premature death process to which they are prone to in PD.
Although the primary causes and molecular pathogenic mechanisms of PD, responsible for dopaminergic neurodegeneration, are still unknown, recent advances in genomic medicine (structural and functional genomics, epigenetics, transcriptomics, proteomics, metabolomics, pharmacogenomics) are allowing us to begin to understand the complex processes leading to the alteration of the nigrostriatal dopaminergic system and consequent premature neuronal death more clearly, prototypical of the dopaminergic neurodegeneration, pharmacogenomics) are allowing us to begin to understand more clearly the complex processes that lead to the alteration of the nigrostriatal dopaminergic system and consequent premature neuronal death. These processes prototypical of the most prevalent neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
What research is being done to better understand and diagnose the disease, develop new treatments, and prevent Parkinson's disease?
- Biomarkers. Discovering ways to identify people who are at risk of developing the disease and to track disease progression. Identifying biomarkers (biological signals that may indicate risk of a disease and improve diagnosis) will accelerate the development of new therapies for PD.
- Clinical studies. Current studies include genetics, biomarkers, experimental therapies, and other treatment options, diagnostic imaging, brain monitoring and movement disorders, deep brain stimulation, and exercise and PD.
- Animal models. These are valuable tools for scientists studying disease mechanisms to develop new treatments for people with PD. A good animal model of PD would have to exhibit some of the main features of the disease, including progressive age-dependent degeneration of vulnerable neuronal populations, intracytoplasmic inclusion formation, and motor impairment.
- Genetics. Better understanding of genetic risk factors is fundamental to the elucidation of PD mechanisms. Current clinical research studies include the genetic connection to memory and motor behaviour, the search for genes that may increase the risk of PD and related neurodegenerative disorders, and the identification of biomarkers for PD.
- Environment. Risk factors such as repeated occupational exposure to certain pesticides and chemical solvents may influence the development of PD. Research looks for environmental risk factors that increase susceptibility to developing PD before the age of 50.
- Cognition and dementia. Mild cognitive impairment is common in PD, sometimes in its early stages, and some people develop dementia later in the course of the disease. Neuroimaging research studies are available to predict which people with Parkinson's may develop cognitive impairment.
- Deep brain stimulation. It is considered a standard treatment option for some people with Parkinson's whose symptoms no longer respond to Parkinson's medications. Research continues to refine the optimal site within the brain to implant the deep brain stimulation electrode to help more people with the disease regain function. Researchers continue to study this intervention and develop ways to improve it.
- Nerve growth factors. Studies to assess the effects of neurotrophic or nerve growth factors in PD.
- Neuroprotective therapies. Basic, clinical, and translational research to protect nerve cells from the damage caused by PD.
- Stem cells. Scientists are exploring various types of cells, including induced pluripotent stem cells (iPSCs), as opportunities to discover drugs for PD.
- Exercise. Exercise routines are often recommended to help people with PD maintain the movement and balance needed for everyday life. A recent study evaluated three different forms of exercise, resistance, stretching and tai chi, and found that tai chi generally provided the greatest improvements in balance and stability for people with mild to moderate PD. A current trial is studying the effects of two levels of exercise in people newly diagnosed with PD.
- Mitochondrial function. The mitochondrion is a cell organelle that is responsible for obtaining energy for the functioning of the cell. Recent research has found that hundreds of genes involved in mitochondrial function are less active in people with PD.
- Motor complications. The motor symptoms of Parkinson's disease become evident as the disease progresses; these symptoms are often difficult to treat. Scientific research studies the safety and efficacy of medications and interventions to alleviate motor symptoms in people with PD.
Parkinson's disease has now become the second most important neurodegenerative disease in developed countries, after Alzheimer's disease, which is the neurocognitive disorder with the greatest socio-economic and socio-health impact in industrialised countries.
The older you get, the greater the likelihood of suffering from Parkinson's disease, making it a serious age-related health problem.
The prevalence of Parkinson's disease ranges from 35.8 cases per 100,000 to 12,500 cases per 100,000, with annual incidence ranging from 1.5 per 100,000 to 346 per 100,000 in different countries, where the disease represents a priority health problem in the adult population. A meta-analysis of data collected worldwide indicates an increase in prevalence, in parallel with age, of 41 per 100,000 between 40 and 49 years, 107 per 100,000 between 50 and 59 years, 175 per 100,000 between 55 and 64 years, 412 per 100,000 between 65 and 74 years, 1,087 per 100,000 between 70 and 79 years, and more than 1,900 per 100,000 above 80 years.
Parkinson's disease has curious geographical characteristics, with a prevalence of 1,601 cases per 100,000 in North America, Europe and Australia, and 646 cases per 100,000 in Asia. The average prevalence above the age of 65 years is 1,600 cases per 100,000; and the peak prevalence is observed above the age of 90 years, with a maximum peak of 4,633 cases per 100,000.
Following Dr Parkinson' s 1817 trial on paralysis agitans, many scientists have contributed over the years to the elucidation of the substrate, causes and possible treatments of Parkinson's disease.
In 1872 Charcot would describe the cardinal symptoms of the disease for the first time, and years later he would propose the first pharmacological treatment based on belladonna alkaloids. Gowers would experiment with cannabis and opium; Barger and Ewens would synthesise dopamine; Holtz would discover the enzyme dopa decarboxylase and so on until the 1960s when L-Dopa was established as the prototypical treatment for Parkinson's disease.
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